Systemic lupus erythematosus (SLE) in adults

Systemic lupus erythematosus (SLE) is a chronic, multisystem autoimmune disease characterised by immune-mediated inflammation affecting virtually any organ. It predominantly affects women of childbearing age (female:male ratio ~9:1), with onset typically between 15 and 45 years. SLE is the paradigmatic systemic autoimmune disease, defined by production of autoantibodies against nuclear antigens, complement consumption, and immune complex-mediated tissue injury. The clinical course is characterised by periods of flare and remission. Untreated or undertreated SLE causes progressive organ damage, particularly lupus nephritis, neuropsychiatric lupus, and cardiovascular disease.

Diagnosis requires ANA positivity (entry criterion) + total score ≥10 points across domains (highest point criterion in each domain counts). Score ≥10 = classified SLE.

SLE results from dysregulated innate and adaptive immune activation, driven by failure of self-tolerance to nuclear antigens. Apoptotic debris and neutrophil extracellular traps (NETs) expose nuclear material that is not adequately cleared, driving sustained type I interferon (IFN) production and autoantibody formation.

Key Pathogenic Mechanisms

• Impaired apoptotic clearance — defective phagocytosis of apoptotic cells exposes nuclear antigens; complement deficiency (C1q, C2, C4 deficiency) predisposes to SLE by impairing immune complex clearance
• Type I interferon pathway — plasmacytoid dendritic cells and NETs drive IFN-α/β production; the "interferon signature" is present in ~75% of SLE patients and correlates with disease activity
• B cell dysregulation — loss of tolerance leads to autoreactive B cells producing anti-dsDNA, anti-Sm, anti-Ro/SSA, anti-La/SSB, and antiphospholipid antibodies
• T cell help — CD4+ T follicular helper cells provide excessive B cell help; Th17/Treg imbalance drives inflammation
• Immune complex deposition — anti-dsDNA/chromatin immune complexes deposit in renal glomeruli, skin, joints, and choroid plexus, activating complement (C3a, C5a) and causing tissue injury
• Complement consumption — low C3, C4 during active lupus nephritis reflects complement consumption by immune complexes

Genetic and Environmental Factors

• HLA associations — HLA-DR2 (DRB1*1501) and HLA-DR3 (DRB1*0301); class II HLA alleles associated with anti-dsDNA and anti-Sm
• Non-HLA genes — STAT4, IRF5, PTPN22, BLK, TREX1, C4A null allele; many shared with other autoimmune diseases
• Hormonal — oestrogen promotes B cell survival and autoantibody production; risk elevated during reproductive years, pregnancy, and OCP use
• Environmental triggers — UV light (photosensitivity, activates keratinocyte apoptosis), EBV infection, drugs (hydralazine, procainamide, minocycline, anti-TNF agents)

SLE is protean in its manifestations. Constitutional symptoms are nearly universal; clinical involvement can affect any organ system. The clinical course is typically relapsing-remitting.

Organ System Manifestations

Lupus Nephritis Classification (ISN/RPS)

• Class I — minimal mesangial lupus nephritis; normal light microscopy
• Class II — mesangial proliferative lupus nephritis; mesangial immune deposits
• Class III — focal lupus nephritis (<50% glomeruli); active or chronic lesions
• Class IV — diffuse lupus nephritis (≥50% glomeruli); most severe; wire-loop lesions
• Class V — membranous lupus nephritis; nephrotic range proteinuria; may coexist with III/IV
• Class VI — advanced sclerosing lupus nephritis; irreversible; >90% globally sclerosed

Diagnosis of SLE requires integration of clinical features with serological, haematological, and urinary findings. Renal biopsy is required to classify lupus nephritis and guide treatment.

• Essential
  ANA (HEp-2 indirect immunofluorescence)

  Entry criterion for 2019 EULAR/ACR criteria. Positive in >95% of SLE. Titre ≥1:80 required. Low-titre ANA is common in the general population and non-specific. Homogeneous pattern correlates with anti-dsDNA; speckled with anti-ENA.
• Essential
  Anti-dsDNA antibodies (ELISA or Crithidia luciliae IIF)

  Highly specific for SLE (~95% specificity). Titre correlates with disease activity and lupus nephritis risk. Serial monitoring — rising titre signals impending flare.
• Essential
  ENA panel (anti-Sm, anti-Ro/SSA, anti-La/SSB, anti-U1 RNP)

  Anti-Sm highly specific for SLE. Anti-Ro/SSA: risk of neonatal lupus and subacute cutaneous lupus. Anti-La/SSB: associated with secondary Sjögren features. Anti-U1 RNP: overlap with MCTD.
• Essential
  Complement C3, C4, CH50

  Low C3 and C4 indicate complement consumption by immune complexes — correlates with active nephritis. Persistently low C4 may indicate C4A null allele (genetic SLE predisposition). Serial monitoring alongside anti-dsDNA.
• Essential
  FBC, UEC, LFTs, CRP, ESR

  Cytopenias (lymphopenia, thrombocytopenia, AIHA); renal function; liver involvement. CRP is typically low-normal in SLE flare (elevated CRP suggests intercurrent infection).
• Essential
  Urinalysis and urine protein:creatinine ratio (urine PCR)

  Every visit in SLE — screen for active nephritis. Haematuria, proteinuria, red cell casts = nephritis until proven otherwise. Urine PCR >100 mg/mmol indicates significant proteinuria.
• Essential
  Antiphospholipid antibody (aPL) panel

  Lupus anticoagulant (most clinically significant), anti-cardiolipin IgG/IgM, anti-β2-glycoprotein I IgG/IgM. Positive aPL in SLE increases thrombosis and pregnancy morbidity risk. Confirm positivity ≥12 weeks apart before diagnosing APS.
• Recommended
  Renal biopsy

  Indicated when lupus nephritis is suspected (haematuria + proteinuria or renal impairment without alternative cause). Essential for ISN/RPS class determination — guides immunosuppression intensity. Organise via rheumatology or nephrology.
• Recommended
  Direct Coombs test and reticulocyte count

  When AIHA suspected — falling Hb + rising reticulocytes + positive Coombs = immune haemolysis.
• Recommended
  Echocardiogram

  For pericardial effusion, myocarditis, Libman-Sacks endocarditis, or pulmonary hypertension assessment. At diagnosis and when cardiopulmonary symptoms present.

SLE severity is assessed by organ involvement, serological activity, and disease activity scores. The SLEDAI-2K (SLE Disease Activity Index) and BILAG are validated tools. Damage accrual is tracked using the SLICC/ACR Damage Index (SDI).

All patients with SLE should receive hydroxychloroquine unless contraindicated. Treatment is tailored to disease activity, organ involvement, and comorbidities. The goal is remission (SLEDAI ≤4 off prednisolone, or ≤2 on ≤5 mg/day prednisolone) or lowest disease activity at minimum immunosuppressive burden.

Specific SLE manifestations require targeted management approaches in addition to systemic immunosuppression.

Lupus Nephritis — Treatment Protocol

• Renal biopsy first — confirm class before committing to induction therapy
• Class III/IV induction: MMF 2–3 g/day + prednisolone 0.5 mg/kg/day (taper over 24 weeks) ± voclosporin; OR Euro-Lupus cyclophosphamide IV + prednisolone
• Class V (membranous) induction: MMF + prednisolone; add voclosporin or calcineurin inhibitor for nephrotic range proteinuria
• Maintenance: MMF 1–2 g/day or azathioprine + low-dose prednisolone for minimum 3–5 years
• ACE inhibitor or ARB — renoprotective; add to reduce proteinuria regardless of blood pressure
• Target: complete renal response (proteinuria <500 mg/24h, stable renal function) by 12 months
• Continue HCQ throughout — reduces nephritis flare rate

Neuropsychiatric SLE (NPSLE)

• Attribution challenge — exclude infection, metabolic, and medication causes before attributing to SLE
• Inflammatory NPSLE (psychosis, myelitis, optic neuritis): high-dose corticosteroids ± cyclophosphamide
• Thrombotic NPSLE (cerebrovascular events, APS): anticoagulation (warfarin or LMWH) rather than intensified immunosuppression

Antiphospholipid Syndrome in SLE

• Primary thromboprophylaxis: low-dose aspirin for aPL-positive SLE patients (particularly lupus anticoagulant positive)
• Arterial thrombosis: warfarin (INR 3–4) preferred over DOACs (DOACs have higher failure rates in APS)
• Venous thrombosis: warfarin (INR 2–3) or LMWH
• Obstetric APS: LMWH + low-dose aspirin throughout pregnancy; commence from positive pregnancy test

Cutaneous SLE

• Photoprotection — SPF 50+ daily; UVA/UVB protection; protective clothing
• Topical corticosteroids or tacrolimus — for localised skin disease
• HCQ — effective for malar rash, SCLE, and discoid lupus; onset 6–12 weeks
• Refractory discoid lupus: add mepacrine or switch to quinacrine; dermatology co-management

Non-pharmacological measures are integral to SLE management — reducing flare triggers, managing comorbidities, and improving quality of life.

Photoprotection

• UV light triggers SLE flares — SPF 50+ broad-spectrum sunscreen daily (even on cloudy days); reapply every 2 hours outdoors
• UV-protective clothing, hats, and avoiding peak UV hours (10am–3pm)
• Photosensitivity affects ~60–80% of SLE patients; particularly important for malar rash and SCLE

Cardiovascular Risk Reduction

• SLE independently accelerates atherosclerosis — 50-fold elevated MI risk in young women with SLE
• Aggressive management of all modifiable cardiovascular risk factors: hypertension (target <130/80), dyslipidaemia (statin therapy), diabetes, smoking cessation
• Annual cardiovascular risk assessment

Bone Protection

• Calcium 600–1200 mg/day + vitamin D 1000–2000 IU/day — all patients on corticosteroids
• Bisphosphonate (alendronate or risedronate) — for patients on prednisolone ≥7.5 mg/day for ≥3 months, or with low bone density
• DXA bone density scan — baseline and 1–2 yearly on prolonged corticosteroids
• Avascular necrosis (AVN) — warn patients about hip/knee/shoulder pain; MRI if suspected

Vaccination and Infection Prevention

• Annual influenza; pneumococcal 13-valent + 23-valent; herpes zoster (recombinant Shingrix ≥50 years or immunosuppressed); COVID-19
• Live vaccines contraindicated on significant immunosuppression
• PCP prophylaxis (cotrimoxazole) — if on prednisone ≥20 mg/day + second immunosuppressant for >4 weeks

Fatigue Management

• Fatigue affects >90% of SLE patients — multifactorial (disease activity, anaemia, poor sleep, depression, deconditioning, medication)
• Regular aerobic exercise — shown to reduce fatigue and improve quality of life; adapt to individual capacity
• Address modifiable contributing factors: treat anaemia, optimise sleep hygiene, manage depression

SLE requires structured, proactive monitoring for disease activity, organ damage, and medication toxicity. Monitoring frequency increases during active disease and induction therapy.

When to Refer Urgently

• Nephrology: Suspected lupus nephritis (haematuria + proteinuria, rising creatinine); renal biopsy planning; resistant nephritis
• Neurology: New seizures, focal neurology, psychosis in SLE — NPSLE evaluation
• Haematology: Severe thrombocytopenia (<20 × 10⁹/L); TTP/HUS presentation; severe AIHA
• Cardiology: Pericardial tamponade, myocarditis, Libman-Sacks endocarditis

Certain patient groups with SLE require modified management approaches.

SLE in Pregnancy

• SLE pregnancies are high-risk — pre-conception counselling by rheumatology and maternal-fetal medicine is mandatory
• Disease should be in remission for ≥6 months before conception; active nephritis at conception markedly increases pregnancy loss and prematurity
• Safe medications in pregnancy: hydroxychloroquine (continue throughout), azathioprine, low-dose prednisolone (≤10 mg/day), low-dose aspirin (for APS and preeclampsia prevention)
• Contraindicated: MMF (teratogenic — stop ≥3 months before conception), MTX, belimumab, cyclophosphamide
• Anti-Ro/SSA positive: fetal cardiac monitoring for congenital heart block (CHB) from 16–26 weeks; CHB risk ~2% per pregnancy (higher with previous CHB infant)
• Monitor for lupus nephritis flare and pre-eclampsia — both cause proteinuria and hypertension; distinguish by clinical and serological activity
• Antiphospholipid antibodies: LMWH + aspirin throughout pregnancy

Male SLE

• SLE in males is often more severe — higher rates of nephritis, neuropsychiatric disease, thrombocytopenia, and damage accrual
• Diagnosis may be delayed due to lower clinical suspicion in males
• Treat according to disease manifestations — no sex-specific therapeutic differences

Drug-Induced Lupus

• Causative drugs: hydralazine, procainamide, isoniazid, minocycline, anti-TNF agents, checkpoint inhibitors (immune-mediated)
• Anti-histone antibodies characteristic; anti-dsDNA negative (except TNF-induced); complement typically normal
• Management: cease offending agent; resolves within weeks to months; rarely requires immunosuppression

Elderly-Onset SLE

• Late-onset SLE (≥50 years) — often Ro-positive, more serositis, less nephritis, more sicca features
• Higher infection risk and drug toxicity — reduce immunosuppression doses; monitor closely
• Drug-induced lupus more common in older patients — always exclude before diagnosing idiopathic SLE

Stewardship in SLE focuses on maximising hydroxychloroquine use, minimising glucocorticoid toxicity, and ensuring appropriate use of immunosuppressants and biologics.

GP Role in SLE Management

• Urinalysis at every visit — non-negotiable; red cell casts = urgent nephritis referral
• Blood pressure control — target <130/80; ACE inhibitor or ARB first-line especially if proteinuria
• Cardiovascular risk management — lipid-lowering, glucose, smoking cessation
• Bone protection — calcium, vitamin D, bisphosphonate for patients on steroids
• Vaccination — ensure influenza, pneumococcal, and zoster vaccines are up to date before immunosuppression escalation
• Medication monitoring — FBC and UEC for azathioprine/MMF/cyclophosphamide; ophthalmology referral for HCQ monitoring

SLE requires lifelong rheumatologist-led follow-up. The treat-to-target (T2T) strategy — targeting remission or low disease activity — is associated with reduced organ damage and improved long-term outcomes.

Long-Term Prognosis

• 10-year survival >90% with modern management — but damage accrual remains a major challenge
• Leading causes of death: infection (early), cardiovascular disease (late), renal failure
• Damage prevention — the primary goal; damage is largely irreversible and cumulative
• Hydroxychloroquine continuation — indefinite; do not stop in remission

• 01
  Fanouriakis A, et al. 2019 update of the EULAR recommendations for the management of systemic lupus erythematosus. Ann Rheum Dis. 2019;78(6):736–745.
• 02
  Aringer M, et al. 2019 EULAR/ACR classification criteria for systemic lupus erythematosus. Arthritis Rheumatol. 2019;71(9):1400–1412.
• 03
  Rovin BH, et al. EULAR recommendations for the management of lupus nephritis. Ann Rheum Dis. 2024;83:19–37.
• 04
  Furie R, et al. Two-year, randomized, controlled trial of belimumab in lupus nephritis. N Engl J Med. 2020;383(12):1117–1128.
• 05
  Arriens C, et al. Voclosporin for active lupus nephritis (AURORA 1 trial). Lancet. 2021;397(10289):2070–2080.
• 06
  Therapeutic Guidelines. Rheumatology. Melbourne: Therapeutic Guidelines Ltd; 2024.
• 07
  Pharmaceutical Benefits Scheme (PBS). Schedule of Pharmaceutical Benefits. Canberra: Department of Health; 2025.
• 08
  Royal Australian College of General Practitioners (RACGP). Clinical guidance — systemic lupus erythematosus. Melbourne: RACGP; 2023.